Improved pharmaceutical formulations

ABSTRACT

A free-flowing solid pharmaceutical formulation comprising one or more active ingredients and a blend comprising sorbitol and liquid paraffin, a package containing the formulation, a process for the manufacture of the formulation and the use of the blend in the formulation.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations, to methodsof making them and to their use in the treatment and prophylaxis ofdiseases in mammals, particularly humans.

BACKGROUND OF THE INVENTION

Pharmaceutical dosage forms which rapidly dissolve when placed in themouth of the patient, thereby delivering the desired dose of thepharmaceutically active substances, are particularly useful when thedosage form can be taken without water. Such dosage forms are generallypreferred by children and old people and also by people withdifficulties in swallowing and/or taking tablets or capsules.

Rapidly dissolving dosage forms are generally prepared using a multistepprocess. Some of these processes use a lyophilization step during whichsolvent is removed from a solution and/or suspension comprising apharmaceutically active substance, carrier material and solvent.

Pharmaceutical formulations manufactured by lyophilization have variousadvantages but also various challenges such as issues of free flow,moisture absorption, bitter taste, dose uniformity and contentuniformity. The present invention aims at overcoming these challenges.

SUMMARY OF THE INVENTION

The present invention provides a novel blend composition of sorbitol andliquid paraffin for use in the improvement of formulation properties ofpharmaceutical formulations in several parameters, i.e. flow properties,moisture protection, antistatic properties and compressibility (CarrIndex). The blend composition may also contain citric acid and has theability to mitigate the taste of bitter drugs.

The present invention thus provides a free-flowing solid pharmaceuticalformulation comprising one or more active ingredients and a blendcomposition comprising or consisting of sorbitol, liquid paraffin andoptionally citric acid.

The present invention further provides a blend, comprising or consistingof sorbitol, liquid paraffin and optionally citric acid, for use in themanufacture of a pharmaceutical formulation comprising one or moreactive ingredients.

The present invention also provides a process for the manufacture of asolid pharmaceutical formulation of the invention comprising:

(a) forming a lyophilized powder by subliming the solvent from apreparation comprising one or more active ingredients and the solvent;(b) forming a blend composition comprising or consisting of sorbitol,liquid paraffin and optionally citric acid;(c) mixing the blend composition obtained in step (b) with thelyophilized powder obtained in step (a).

FIGURES

FIG. 1 compares the Compressibility Index (Carr Index) of theformulations of Example 1 and Comparative Examples A-E.

FIG. 2 compares the Hausner Ratio of the formulations of Example 1 andComparative Examples A-E.

FIG. 3 depicts the % Moisture Content of the formulations of Example 1and Comparative Examples A-E as a function of storage time.

FIG. 4 compares the % Residual Content of the formulations of Example 1and Comparative Examples A-E.

FIG. 5 is a photograph of a stick pack of the invention.

FIG. 6 compares the Compressibility Index (Carr Index) of theformulations of Example 2 and Comparative Examples F-K.

FIG. 7 compares the Hausner Ratio of the formulations of Example 2 andComparative Examples F-K.

FIG. 8 depicts the % Moisture Content of the formulations of Example 2and Comparative Examples F-K as function of storage time.

FIG. 9 compares the % Residual Content of the formulations of Example 2and Comparative Examples F-K.

FIG. 10 compares the Compressibility Index (Carr Index) of theformulations of Example 3-4 and Comparative Examples L-Q.

FIG. 11 compares the Hausner Ratio of the formulations of Example 3-4and Comparative Examples L-Q.

FIG. 12 depicts the % Moisture Content of the formulations of Example3-4 and Comparative Examples L-Q as function of storage time.

FIG. 13 compares the % Residual Content of the formulations of Example3-4 and Comparative Examples L-Q

FIG. 14 compares the Compressibility Index (Carr Index) of theformulations of Example 5 and Comparative Examples R-W.

FIG. 15 compares the Hausner Ratio of the formulations of Example 5 andComparative Examples R-W.

FIG. 16 depicts the % Moisture Content of the formulations of Example 5and Comparative Examples R-W as function of storage time.

FIG. 17 compares the % Residual Content of the formulations of Example 5and Comparative Examples R-W

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel blend composition of sorbitol andliquid paraffin for use in the improvement of formulation properties ofpharmaceutical formulations in several parameters, i.e. flow properties,moisture protection, antistatic properties and compressibility. Theblend composition may also contain citric acid and has ability tomitigate the taste of bitter drugs.

The novel blend, when mixed with lyophilized powder, provides apharmaceutical formulation with improved properties, e.g., flowproperties, moisture protection, antistatic properties andcompressibility.

The present invention thus provides a free-flowing solid pharmaceuticalformulation comprising one or more active ingredients and a blendcomposition comprising or consisting of sorbitol, liquid paraffin andoptionally citric acid.

The formulation preferably comprises 0.01% to 30% by weight of one ormore active ingredients, 70% to 99.99% by weight of the blendcomposition, and 0% to 30% by weight of one or more otherpharmaceutically acceptable excipients. More preferably, the formulationcomprises 0.1% to 28% by weight of one or more active ingredients, 72%to 99.9% by weight of the blend composition, and 5% to 30% by weight ofone or more other pharmaceutically acceptable excipients. In anembodiment of the invention, the formulation is obtained by a processincluding steps of forming the blend composition by blending sorbitol,liquid paraffin and optionally citric acid, and adding the blendcomposition to the active ingredient(s), which is preferably alyophilized powder.

The present invention further provides a blend composition comprising orconsisting of sorbitol, liquid paraffin and optionally citric acid foruse in the manufacture of a pharmaceutical formulation comprising one ormore active ingredients. The blend composition preferably comprises 95to 99.9% by weight of sorbitol, 0.1% to 5% by weight of liquid paraffin,and 0 to 4% by weight of citric acid. More preferably, the blendcomposition comprises 96 to 99.5% by weight of sorbitol, 0.5% to 4% byweight of liquid paraffin, and 0.5 to 2% by weight of citric acid. Inone embodiment, the blend composition consists of the indicatedcomponents, in the indicated preferred and more preferred proportions.

The present invention also provides a process for the manufacture of asolid pharmaceutical formulation of the invention comprising:

(a) forming a lyophilized powder by subliming the solvent from apreparation comprising one or more active ingredients and the solvent;(b) forming a blend composition comprising or consisting of sorbitol,liquid paraffin and optionally citric acid;(c) mixing the blend composition obtained in step (b) with thelyophilized powder obtained in step (a).

The process of the invention allows obtaining a solid pharmaceuticalformulation in the form of a free-flowing powder.

Preferred proportions of active ingredient(s), sorbitol, liquidparaffin, citric acid and blend composition in the process of thepresent invention are the same as in the pharmaceutical formulation ofthe present invention.

The solvent used in the preparation to be lyophilized, comprising activeingredient(s) and solvent, typically is water.

The terms “active ingredient” and “pharmaceutically active ingredient”are used interchangeably herein.

The pharmaceutical formulation of the present invention comprises one ormore pharmaceutically active ingredients. They may be selected from,e.g., oligopeptides, polypeptides (proteins), nucleotides,polynucleotides and “small molecules”. Non-limiting examples ofpharmaceutically active ingredients which can be used in the presentinvention are analgesics, alpha blockers, anti-allergy agents,anti-asthma agents, anti-rhinitis agents, anti-uticaria agents,anti-inflammatory agents, anti-arrhythmic agents, anti-bacterial agents,anti-psychotics, anti-diabetics, anti-diuretics, anti-epileptics,anti-fungal agents, anti-gout agents, anti-hypertensive agents,anti-incontinence agents, anti-migraine agents, anti-muscarinic agentsand immunosuppressants, antivirals, anxiolytics, sedatives, hypnoticsand neuroleptics, anti-benign hyperplasia (BPH agents), decongestants,diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents,histamine receptor antagonists, infertility agents, endometriosisagents, hormone replacement therapy agents, lipid regulating agents,local anesthetics, neuromuscular agents, motion sickness agents,nutritional agents, oral vaccines, proteins, peptides and recombinantdrugs, proton pump inhibitors, anti-schizophrenia agents, hormones,contraceptives, seizure/panic disorder agents, sexual dysfunction (maleand female) agents and so forth.

Specific non-limiting examples of these active ingredients are:

-   -   Anti-allergics: desloratadine, loratadine, Montelukast,        Montelukast sodium, Cetirizin, Fexofenadin, Ebastine.    -   Alfa blockers: Tamsulosin, Silodosin    -   Analgesics and anti-inflammatory agents: aspirin, aloxiprin,        auranofin, azapropazone, benorylate, diflunisal, etodolac,        fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen,        indomethacin, ketoprofen, meclofenamic acid, mefenamic acid,        nabumetone, naproxen, oxaprozin, oxyphenbutazone,        phenylbutazone, piroxicam, sulindac, paracetamol.    -   Anti-arrhythmic agents: amiodarone HCl, disopyramide, flecainide        acetate, quinidine sulphate.    -   Anti-bacterial agents: benethamine penicillin, cinoxacin,        ciprofloxacin HCl, clarithromycin, do fazimine, cloxacillin,        demeclocycline, doxycycline, erythromycin, ethionamide,        imipenem, nalidixic acid, nitrofurantoin, rifampicin,        spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,        sulphacetamide, sulphadiazine, sulphafurazole,        sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim.    -   Anti-psychotics: amoxapine, ciclazindol, maprotiline HCl,        mianserin HCl, nortriptyline HCl, trazodone HCl, trimipramine        maleate.    -   Anti-diabetics: acetohexamide, chlorpropamide, glibenclamide,        gliclazide, glipizide, tolazamide, tolbutamide.    -   Anti-diuretics: desmopressin and its analog, desmopressin        acetate.    -   Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin,        methoin, methsuximide, methylphenobarbitone, oxcarbazepine,        paramethadione, phenacemide, phenobarbitone, phenytoin,        phensuximide, primidone, sulthiame, valproic acid.    -   Anti-fungal agents: amphotericin, butoconazole nitrate,        clotrimazole, econazole nitrate, fluconazole, flucytosine,        griseofulvin, itraconazole, ketoconazole, miconazole, natamycin,        nystatin, sulconazole nitrate, terbinafine HCl, terconazole,        tioconazole, undecenoic acid.    -   Anti-gout agents: allopurinol, probenecid, sulphinpyrazone.    -   Anti-hypertensive agents: amlopidine, benidipine, darodipine,        dilitazem HCl, diazoxide, felodipine, guanabenz acetate,        indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine,        nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine,        terazosin HCl.    -   Anti-migraine agents: rizatriptan, dihydroergotamine mesylate,        ergotamine tartrate, methysergide maleate, pizotifen maleate,        sumatriptan succinate, caffeine.    -   Anti-muscarinic agents: oxybutinin, tolterodin, atropine,        benzhexol HCl, biperiden, ethopropazine HCl, hyoscine butyl        bromide, hyoscyamine, mepenzolate bromide, orphenadrine,        oxyphencylcimine HCl, tropicamide.    -   Anti-rhinitis agents, anti-uticaria agents: Cetirizin,        fexofenadin, ebastine, loratadine, montelukast.    -   Antivirals: acyclovir, amantadine hydrochloride, famciclovir,        zidovadine, didanosine, zalcitabine, foscarnet sodium.    -   Anxiolytic agents, sedatives, hypnotics and neuroleptics:        alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,        bromperidol, brotizolam, butobarbitone, carbromal,        chlordiazepoxide, Chlorpheniramine, chlormethiazole,        chlorpromazine, clobazam, clonazepan, clotiazepam, clozapine,        diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,        fluopromazine, flupenthixol decanoate, fluphenazine decanoate,        flurazepam, haloperidol, lorazepam, lormetazepam, medazepam,        meprobamate, methaqualone, midazolam, nitrazepam, oxazepam,        pentobarbitone, perphenazine phenylephrine, pimozide,        prochlorperazine, pseudoephedrineHCL, sulpride, temazepam,        thioridazine, triazolam, zopiclone.    -   Contraceptives: clomiphene citrate, danazol, desogestrel,        ethinyloestradiol, ethynodiol, ethynodiol diacetate,        levonorgestrel, medroxyprogesterone acetate, mestranol,        methyltestosterone, norethisterone, norethisterone enanthate,        norgestrel, estradiol, conjugated estrogens, dydrogesterone,        progesterone, stanozolol, stilboestrol, testosterone, tibolone.    -   Decongestants: pseudoephedrine hydrochloride.    -   Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide,        chlorothiazide, chlorthalidone, ethacrynic acid, frusemide,        metolazone, spironolactone, triamterene.    -   Enzymes: pancreatin, pepsin, lipase.    -   Epilepsy: Gabapentin    -   Anti-parkinsonian agents: bromocriptine mesylate, lysuride        maleate, selegiline, para-fluoroselegiline, lazabemide,        rasagiline, 2-BUMP [N-(2-butyl)-N-methylpropargylamine], M-2-PP        [N-methyl-N-(2-pentyl)-propargylamine], MDL-72145        [beta-(fluoromethylene)-3,4-dimethoxy-benzeneethanamine],        mofegiline, apomorphine, N-propylnoraporphine, cabergoline,        metergoline, naxagolide, pergolide, piribedil, ropinirole,        terguride, quinagolide.    -   Gastro-intestinal agents: bisacodyl, cimetidine, cisapride,        diphenoxylate HCl, domperidone, metoclopramide, famotidine,        loperamide, mesalazine, nizatidine, esomeprazole, metopimazine,        pantoprazole, ondansetron HCl, Granisetron, tropisetron,        dolasetron, ranitidine HCl, sulphasalazine. Lanzoprazole.    -   Histamine Receptor Antagonists: acrivastine, astemizole,        cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate,        flunarizine HCl, loratadine, meclozine HCl, oxatomide,        terfenadine, triprolidine.    -   Hormones: Human Growth hormone (HGH), Follicle Stimulating        Hormone (FSH), Gonadotropin-releasing hormone (GnRH) agonists or        antagonists, nafarelin Triptorelin, cetrorelix, atosiban.    -   Hormone replacement therapy agents: dydrogesterone.    -   Anti-hypertension agents: Enalapril.    -   Lactation agents: Oxytocin, oxytocin agonists.    -   Lipid regulating agents: bezafibrate, clofibrate, fenofibrate,        gemfibrozil, probucol.    -   Local anaesthetics: amethocaine, amylocaine, benzocaine,        bucricaine, bupivacaine, butacaine, butanilicaine, butoxycaine,        butyl aminobenzoate, carticaine, chloroprocaine, cinchocaine,        clibucaine, clormecaine, coca, cocaine, cyclomethycaine,        dimethisoquin, diperodon, dyclocaine, ethyl chloride, ethyl        p-piperidinoacetylaminobenzoate, etidocaine, hexylcaine,        isobutamben, ketocaine, lignocaine, mepivacaine, meprylcaine,        myrtecaine, octacaine, oxethazaine, oxybuprocaine,        parethoxycaine, pramoxine, prilocaine, procaine, propranocaine,        propoxycaine, proxymetacaine, ropivacaine, tolycaine, tricaine,        trimecaine, vadocaine.    -   Motion sickness agents: diphenhydramine.    -   Neuro-muscular agents: pyridostigmine.    -   Nonsteroidal antiandrogens: Enzalutamide.    -   Nutritional agents: betacarotene, vitamins, such as vitamin A,        vitamin B₂, vitamin D, vitamin E, vitamin K, minerals.    -   Oral vaccines: to prevent or reduce the symptoms of diseases        such as Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping        Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes,        Typhoid, HIV, AIDS, Measles, Lyme disease, Traveller's Diarrhea,        Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies,        Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaires        Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina        Haemorrhegic Fever, Caries, Chagas Disease, Urinary Tract        Infection caused by E. coli, Pneumococcal Disease, Mumps,        Chikungunya, Hay fever, Asthma, Rheumatoid Arthritis,        Carcinomas, Coccidiosis, Newcastle Disease, Enzootic pneumonia,        Feline leukemia, Atrophic rhinitis, Erysipelas, Foot and Mouth        disease and Swine pneumonia, or to prevent or reduce the        symptoms of diseases caused by Vibrio species, Salmonella        species, Bordetella species, Haemophilus species, Toxoplasmosis        gondii, Cytomegalovirus, Chlamydia species, Streptococcal        species, Norwalk Virus, Escherischia coli, Helicobacter pylori,        Rotavirus, Neisseria gonorrhae, Neisseria meningiditis,        Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus,        Pneumocystis carini, Herpes simplex, Clostridia species,        Respiratory Syncytial Virus, Klebsiella species, Shigella        species, Pseudomonas aeruginosa, Parvovirus, Campylobacter        species, Rickettsia species, Varicella zoster, Yersinia species,        Ross River Virus, J. C. Virus, Rhodococcus equi, Moraxella        catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica,        BCG.    -   Agents for voiding dysfunctions: Tamsulosin, trospium chloride,        tolterodine, oxybutynin, Solifenacin.    -   Proteins, peptides and recombinant drugs: recombinant hormones        and iso-hormones, recombinant cytokines, recombinant        plasminogens, TNF receptor fusion protein, monoclonal        antibodies, nucleic acids, antisense oligonucleotides,        oligonucleotides, glycoproteins and adhesion molecules,        Calcitonin, octreotide, insulin and insulin analogs, etanercept,        pegfilgrastim, liraglutide, bivalirudin, nesiritide, ceruletide,        bentiromide, exenatide, gonadorelin, enfuvirtide, vancomycin,        icatibant, secretin, leuprolide, glucagon recombinant, oxytocin,        sermorelin, gramicidin D, Insulin recombinant, capreomycin,        vasopressin, cosyntropin, bacitracin, abarelix, vapreotide,        thymalfasin, mecasermin, teriparatide, corticotropin,        pramlintide.    -   Phosphate Binders: Sevelamer.    -   Sexual dysfunction agents: Cabergolin, oxytocin, tadalafil,        sildenafil, vardenafil.    -   Stimulants: amphetamine, dexamphetamine, dexfenfluramine,        fenfluramine.

In a specific embodiment, the active ingredient of a formulation of theinvention is selected from the group consisting of desloratadine,montelukast, solifenacin, silodosin, sildenafil and any pharmaceuticallyacceptable salt thereof.

In a specific embodiment, the active ingredient of a formulation of theinvention is desloratadine.

In a specific embodiment, the active ingredient of a formulation of theinvention is sildenafil.

In a specific embodiment, the active ingredient of a formulation of theinvention is solifenacin.

In addition to the components discussed above, the formulation may alsoinclude other excipients (auxiliary agents, accessory agents) such as,but not limited to fillers, thickeners (including but not limited toguar gum and xanthan gum), binders, diluents, lubricants, pH adjustingagents, protecting agents, viscosity enhancers, wicking agents,non-effervescent disintegrants, effervescent disintegrants, surfactants,anti-oxidants, wetting agents, colorants, flavoring agents,taste-masking agents, sweeteners, preservatives and so forth.

A suitable route of administration for a dosage form of the presentinvention is oral administration.

In one embodiment, a pharmaceutical formulation of the invention can beadministered to a patient in the form of a powder.

In another aspect, a pharmaceutical formulation of the invention iscontained in a package dispensing single doses of the formulation, alsonamed a unit dosage form. Non-limiting examples of a package/unit dosageform are a sachet and a stick pack.

In another embodiment, a pharmaceutical formulation of the invention,e.g., in the form of a powder, is packed in a multi-dosage form, i.e. adosage form allowing withdrawing multiple doses of arbitrary size.Non-limiting examples of a multi-dosage form are a bottle and any othercontainer capable of holding a powder.

A patient administered with a free-flowing powder formulation of theinvention will be certain that he receives the entire dosage, i.e. therewill be no residue left in the package/unit dosage form.

In one embodiment, the oral administration is carried out by emptying asachet, stick pack or (any other) unit pack containing the powder ontothe tongue and swallowing the content.

In another embodiment, the oral administration is carried out bydissolving the powder in a solvent (e.g. a glass of water) and thendrink the solution.

The exact dose and regimen of administration of the dosage form willnecessarily depend upon the therapeutic effect to be achieved and mayvary with the particular active ingredient, the route of administration,and the age and condition of the individual subject to whom theformulation is to be administered. At times patients may be instructedto take two or any other number of unit dosage forms, e.g. stick packs,in a single administration or at times only a portion, such as half or aquarter, of the unit dosage form in a single administration.

The formulations of the invention are unique in that they have improvedflow properties, moisture content, antistatic properties andcompressibility.

The pharmaceutical formulation of the invention may be obtained by:

(a) forming a lyophilized powder by subliming the solvent (e.g. water),for example in a freeze drying process, from a preparation thatcomprises the active ingredient(s) and the solvent;(b) forming a blend composition comprising sorbitol and liquid paraffin.The blend composition may optionally contain citric acid;(c) mixing the blend composition with the lyophilized powder obtained instep (a) to obtain a pharmaceutical composition with improved flowproperties, moisture protection, antistatic properties andcompressibility.

According to one embodiment, the resulting free flowing composition isintroduced into a stick pack.

According to another embodiment, the resulting free flowing compositionis introduced into a sachet.

The free flowing blend composition of sorbitol and liquid paraffin ismixed with a lyophilized powder by methods known in the art such asgeometric mixing or mixing with any type of blender.

EXAMPLES

The invention is further described in the following examples, which arenot in any way intended to limit the scope of the inventions as claimed.

Materials and Methods

Material Manufactured by Supplied by Polacrillin Potassium Dow FranceS.A.S Colorcon India (resin) Maltodextrin Roquette France Signet IndiaCitric acid Merck Merck Talc Imerys Talc Signet India Magnesium stearateSun-shine Sun-shine Liquid paraffin Ashwini chemicals Ashwini chemicalspvt. Ltd. pvt. Ltd. Sorbitol Roquette Signet India Desloratadine EnaltecEnaltec Sodium Hydroxide Merck Merck Mannitol Roquette France SignetIndia Hydroxypropyl cellulose L Ashland Ashland Tartaric acid pelletsIdeal cures Ideal cures Sildenafil citrate Rakshit drugs Rakshit drugsSolifenacin MSN Lab MSN Lab

Example 1: Placebo Formulation

A (placebo) formulation was prepared using the following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Resin 20.0 2Maltodextrin 77.0 3 Citric acid 3.0 4 Water q.s. to 400 g BlendComposition 5 Sorbitol 394.5 6 Citric acid 3.0 7 Liquid paraffin 2.5

Manufacturing Procedure: I. Lyophilized Granules

-   -   1. Citric acid was dissolved in 200 g of water using a        magnetic/overhead stirrer for 5 minutes.    -   2. Resin was added under continuous stirring and the dispersion        formed was kept under stirring for 1 hour.    -   3. Maltodextrin was added under continuous stirring.    -   4. The final weight of the solution/dispersion was made to 400 g        using purified water.    -   5. Mixing of the solution/dispersion was continued for 10        minutes in a magnetic/overhead stirrer.    -   6. This solution/dispersion was filled in stainless steel tray        and freeze-dried in a lyophilizer.    -   7. After complete freeze drying, the lyophilized cake was sieved        through a #40 sieve to obtain the lyophilized granules.

II. Blend Composition

-   -   8. Sorbitol was passed through a #40 sieve and mixed with        crushed and sieved citric acid in a double cone blender for 2        minutes at 10 RPM.    -   9. Liquid paraffin was added dropwise to 40 g of the mixture        from step 8, and mixed manually to obtain a uniformly        distributed blend composition.    -   10. The blend composition was sieved through a #60 sieve and        then mixed with remaining mixture from step 8 using a double        cone blender for 3 minutes at 10 RPM to obtain the final blend        composition.

III. Formulation

-   -   11. The lyophilized granules from step 7 were mixed with the        final blend composition from step 10 in a double cone blender        for 5 minutes at 10 RPM to obtain the free flowing (placebo)        composition.    -   12. The free flowing composition was filled into stick packs and        sealed, at 500 mg per stick pack (see FIG. 5).

Example 2: Desloratadine Composition

A formulation of desloratadine was prepared using the followingingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Desloratadine 10.0 2Resin 20.0 3 Maltodextrin 67.0 4 Citric acid 3.0 5 Water q.s. to 400 gBlend Composition 6 Sorbitol 394.5 7 Citric acid 3.0 8 Liquid paraffin2.5

Manufacturing Procedure I. Lyophilized Granules

-   -   1. Citric acid was dissolved in 200 g of water using a        magnetic/overhead stirrer for 5 minutes.    -   2. Desloratadine was added under continuous stirring using a        magnetic/overhead stirrer.    -   3. Resin was added under continuous stirring and the dispersion        formed was kept under stirring for 1 hour.    -   4. Maltodextrin was added under continuous stirring.    -   5. The final weight of the solution/dispersion was made to 400 g        using purified water.    -   6. Mixing of the solution/dispersion was continued for 10        minutes in a magnetic/overhead stirrer.    -   7. This solution/dispersion was filled in stainless steel tray        and freeze-dried in a lyophilizer.    -   8. After complete freeze drying, the lyophilized cake was sieved        through a #40 sieve to obtain the lyophilized granules.

II. Blend Composition

-   -   9. Sorbitol was passed through a #40 sieve and mixed with        crushed and sieved citric acid in a double cone blender for 2        minutes at 10 RPM.    -   10. Liquid paraffin was added dropwise to 40 g of the mixture        from step 9, and mixed manually to obtain a uniformly        distributed blend composition.    -   11. The blend composition was sieved through a #60 sieve and        then mixed with remaining mixture from step 9 using a double        cone blender for 3 minutes at 10 RPM to obtain the final blend        composition.

III. Formulation

-   -   12. The lyophilized granules from step 8 were mixed with the        final blend composition from step 11 in a double cone blender        for 5 minutes at 10 RPM to obtain the free flowing desloratadine        formulation.    -   13. The free flowing composition was filled into stick packs and        sealed, at 500 mg per stick pack (see FIG. 5).

Comparative Example A

A granule formulation was prepared essentially as described in Example 1using the following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) 1 Resin 33.0 2Maltodextrin 129.0 3 Citric acid 8.0 4 Water q.s. to 200 g

Comparative Example B

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 1 by using a blend composition containing talc andthe other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Resin 33.0 2Maltodextrin 127.0 3 Citric acid 5.0 4 Water q.s. to 200 g BlendComposition 5 Citric acid 3.0 6 Talc 2.5

Comparative Example C

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 1 by using a blend composition containing Magnesiumstearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Resin 33.0 2Maltodextrin 127.0 3 Citric acid 5.0 4 Water q.s. to 200 g BlendComposition 5 Citric acid 3.0 6 Magnesium stearate 2.5

Comparative Example D

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 1 by using a blend composition containing Talc,Magnesium stearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Resin 33.0 2Maltodextrin 127.0 3 Citric acid 5.0 4 Water q.s. to 200 g BlendComposition 5 Citric acid 3.0 6 Talc 1.3 7 Magnesium stearate 1.3

Comparative Example E

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 1 by using a blend composition containing onlyliquid paraffin and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Resin 33.0 2Maltodextrin 127.0 3 Citric acid 5.0 4 Water q.s. to 200 g BlendComposition 5 Citric acid 3.0 6 Liquid paraffin 2.5

Comparative Example F

A granule formulation was prepared essentially as described in Example 2using the following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) 1 Desloratadine 16.7 2Resin 33.40 3 Maltodextrin 111.89 4 Citric acid 8.0 5 Water q.s. to 668g

Comparative Example G

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 2 by using a blend composition containing talc andthe other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Desloratadine 16.45 2Resin 33.0 3 Maltodextrin 110.0 4 Citric acid 5.0 5 Water q.s. to 658 gBlend Composition 6 Citric acid 3.0 7 Talc 2.5

Comparative Example H

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 2 by using a blend composition containing Magnesiumstearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Desloratadine 16.45 2Resin 33.0 3 Maltodextrin 110.0 4 Citric acid 5.0 5 Water q.s. to 658 gBlend Composition 6 Citric acid 3.0 7 Magnesium stearate 2.5

Comparative Example I

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 2 by using a blend composition containing Talc,Magnesium stearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Desloratadine 16.45 2Resin 33.0 3 Maltodextrin 110.0 4 Citric acid 5.0 5 Water q.s. to 658 mgBlend Composition 6 Citric acid 3.0 7 Talc 1.3 8 Magnesium stearate 1.3

Comparative Example J

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 2 by using a blend composition containing onlyliquid paraffin and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Desloratadine 16.45 2Resin 33.0 3 Maltodextrin 127.0 4 Citric acid 5.0 5 Water q.s. to 200 gBlend Composition 6 Citric acid 3.0 7 Liquid paraffin 2.5

Comparative Example K

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 2 by using a blend composition containing onlySorbitol and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Desloratadine 10.0 2Resin 20.0 3 Maltodextrin 67.0 4 Citric acid 3.0 5 Water q.s. to 400 gBlendComposition 6 Sorbitol 400.0

Example 3: Sildenafil Composition

A formulation of sildenafil was prepared using the followingingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Sorbitol 604.87 7 Citric acid64.63 8 Liquid paraffin 3.0

Manufacturing Procedure I. Lyophilized Granules

-   -   1. Sodium hydroxide was dissolved in 370 mL of purified water        under stirring on overhead stirrer for 10 min at 1000 RPM    -   2. Sildenafil citrate was dispersed uniformly in the solution of        step 1 under stirring for 30 min.    -   3. The dispersion obtained in step 2 was homogenized at 10000        RPM for 60 min using homogenizer and overhead stirrer.    -   4. Hydroxypropyl cellulose L was dissolved in water (166.5 g)        and the solution was added to dispersion of step 2 under        stirring.    -   5. Mannitol was added to the dispersion.    -   6. The final weight of the solution/dispersion was made to 1000        g using purified water.    -   7. Mixing of the solution/dispersion was continued for 10        minutes in a magnetic/overhead stirrer.    -   8. This solution/dispersion was filled in stainless steel tray        and freeze-dried in a lyophilizer.    -   9. After complete freeze drying, the lyophilized cake was sieved        through a #40 sieve to obtain the lyophilized granules.

II. Blend Composition

-   -   10. Sorbitol was passed through a #40 sieve and mixed with        crushed and sieved citric acid in a double cone blender for 2        minutes at 10 RPM.    -   11. Liquid paraffin was added dropwise to 40 g of the mixture        from step 10, and mixed manually to obtain a uniformly        distributed blend composition.    -   12. The blend composition was sieved through a #60 sieve and        then mixed with remaining mixture from step 9 using a double        cone blender for 3 minutes at 10 RPM to obtain the final blend        composition.

III. Formulation

-   -   13. The lyophilized granules from step 9 were mixed with the        final blend composition from step 12 in a double cone blender        for 5 minutes at 10 RPM to obtain the free flowing Sildenafil        Citrate formulation.    -   14. The free flowing formulation was filled into stick packs and        sealed, at 500 or 1000 mg per stick pack (see FIG. 5).

Example 4: Sildenafil Composition

A formulation of Sildenafil was prepared essentially as described inExample 3 using the following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Sorbitol 604.87 7 Tartaric acidpellets 64.63 8 Liquid paraffin 3.00

Comparative Example L

A granule formulation was prepared essentially as described in Example 3using the following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g

Comparative Example M

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 3 by using a blend composition containing talc andthe other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Citric acid 64.63 7 Talc 3.0

Comparative Example N

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 3 by using a blend composition containing Magnesiumstearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Citric acid 64.63 7 Magnesiumstearate 3.0

Comparative Example 0

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 3 by using a blend composition containing Talc,Magnesium stearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Citric acid 64.63 7 Talc 1.50 8Magnesium stearate 1.50

Comparative Example P

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 3 by using a blend composition containing liquidparaffin and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Citric acid 64.63 7 Liquidparaffin 3.0

Comparative Example Q

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 3 by using a blend composition containing Sorbitoland the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Sildenafil Citrate140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 4 HPC-L 4.0 5 PurifiedWater q.s to 1000 g Blend Composition 6 Sorbitol 604.87

Example 5: Solifenacin Composition

A formulation of Solifenacin was prepared using the followingingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Solifenacin 10.0 2Polacrillin Potassium (Resin) 20.0 3 Maltodextrin 67.0 4 Citric acid 3.05 Water q.s. to 400 g Blend Composition 6 Sorbitol 394.5 7 Citric acid3.0 8 Liquid paraffin 2.5

Manufacturing Procedure I. Lyophilized Granules

-   -   1. Solifenacin was dissolved in 140 g of water using a        magnetic/overhead stirrer for 5 minutes.    -   2. Citric acid was added under continuous stirring using a        magnetic/overhead stirrer.    -   3. Resin was added under continuous stirring and the dispersion        formed was kept under stirring for 1 hour.    -   4. Maltodextrin was dissolved in 140 g of water in separate        beaker & then added in to step 3 under continuous stirring.    -   5. The final weight of the solution/dispersion was made to 400 g        using purified water.    -   6. Mixing of the solution/dispersion was continued for 10        minutes in a magnetic/overhead stirrer.    -   7. This solution/dispersion was filled in stainless steel tray        and freeze-dried in a lyophilizer.    -   8. After complete freeze drying, the lyophilized cake was sieved        through a #40 sieve to obtain the lyophilized granules.

II. Blend Composition

-   -   9. Sorbitol was passed through a #40 sieve and mixed with        crushed and sieved citric acid in a double cone blender for 2        minutes at 10 RPM.    -   10. Liquid paraffin was added dropwise to 40 g of the mixture        from step 9, and mixed manually to obtain a uniformly        distributed blend composition.    -   11. The blend composition was sieved through a #60 sieve and        then mixed with remaining mixture from step 9 using a double        cone blender for 3 minutes at 10 RPM to obtain the final blend        composition.

III. Formulation

-   -   12. The lyophilized granules from step 8 were mixed with the        final blend composition from step 11 in a double cone blender        for 5 minutes at 10 RPM to obtain the free flowing Solifenacin        formulation.    -   13. The free flowing composition was filled into stick packs and        sealed, at 500 mg per stick pack (see FIG. 5).

Comparative Example R

A granule formulation was prepared essentially as described in Example 5using the following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) 1 Solifenacin 16.5 2Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 4 Citric acid5.0 5 Water q.s. to 682 g

Comparative Example S

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 5 by using a blend composition containing talc andthe other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Solifenacin 16.5 2Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 4 Citric acid5.0 5 Water q.s. to 682 g Blend Composition 6 Citric acid 3.0 7 Talc 2.5

Comparative Example T

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 5 by using a blend composition containing Magnesiumstearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Solifenacin 16.5 2Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 4 Citric acid5.0 5 Water q.s. to 682 g Blend Composition 6 Citric acid 3.0 7Magnesium stearate 2.5

Comparative Example U

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 5 by using a blend composition containing Talc,Magnesium stearate and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Solifenacin 16.5 2Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 4 Citric acid5.0 5 Water q.s. to 682 g Blend Composition 6 Citric acid 3.0 7 Talc 1.38 Magnesium stearate 1.3

Comparative Example V

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 5 by using a blend composition containing liquidparaffin and the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Solifenacin 16.5 2Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 4 Citric acid5.0 5 Water q.s. to 682 g Blend Composition 6 Citric acid 3.0 7 Liquidparaffin 2.5

Comparative Example W

A comparative pharmaceutical formulation was prepared essentially asdescribed in Example 5 by using a blend composition containing Sorbitoland the other following ingredients:

Ingredients Quantity per 1000 Stick Packs (g) Lyophilized Granulesprepared from liquid composition composed of: 1 Solifenacin 10.0 2Polacrillin Potassium (Resin) 20.0 3 Maltodextrin 67.0 4 Citric acid 3.05 Water q.s. to 400 g Blend Composition 6 Sorbitol 400.0

Example 6: Bulk Density & Tapped Density Results

Bulk and tapped density are important to understand flow properties offormulations. The bulk density of a material is the ratio of the mass tothe volume (including the interparticulate void volume) of an untappedpowder sample. The tapped density is an increased bulk density attainedafter mechanically tapping a container containing the powder sample. Thetapped density is obtained by mechanically tapping a graduated cylindercontaining the sample until little further volume change is observed.Because the interparticulate interactions influencing the bulkingproperties of a powder are also the interactions that interfere withpowder flow, a comparison of the bulk and tapped densities can give ameasure of the relative importance of these interactions in a givenpowder. Such a comparison is often used as an index of the ability ofthe powder to flow, for example the Compressibility Index or the HausnerRatio:

Compressibility Index (Carr Index):

$\frac{100\left( {V_{0} - V_{f}} \right)}{V_{0}}$

Hausner Ratio:

$\frac{V_{0}}{V_{f}}$

V₀=unsettled apparent volume (bulk volume) V_(f)=final tapped volume

The lower the values of Compressibility Index and Hausner Ratio, thebetter the flow properties of the powder.

Procedure for Determining Bulk Density:

According to US Pharmacopoeia (USP) Chapter <616>, Method I, using a100-mL cylinder readable to 1 mL and an amount of powder such that itsuntapped apparent volume is between 50 and 100 mL.

Procedure for determining tapped density:

According to US Pharmacopoeia (USP) Chapter <616>, Method I, with thefollowing details:

-   -   A 100-mL graduated cylinder (readable to 1 mL) weighing 130±16 g        is mounted on a holder weighing 240±12 g.    -   10, 500, and 1250 taps on the powder sample are conducted and        corresponding volumes V₁₀, V₅₀₀, and V₁₂₅₀ to the nearest        graduated unit are measured.    -   If the difference between V₅₀₀ and V₁₂₅₀ is less than or equal        to 1 mL, V₁₂₅₀ is the tapped volume.    -   If the difference between V₅₀₀ and V₁₂₅₀ exceeds 1 mL, the        measurement is repeated in increments such as 1250 taps, until        the difference between succeeding measurements is less than or        equal to 1 mL.

Results:

Bulk Tapped Density Density Carr Hausner Formulations (g/ml) (g/ml)Index Ratio Example 1 0.476 0.652 26.984 1.370 Example 2 0.50 0.64 21.671.28 Comparative Example A 0.192 0.333 42.308 1.733 Comparative ExampleB 0.200 0.341 41.333 1.705 Comparative Example C 0.231 0.385 40.0001.667 Comparative Example D 0.208 0.366 43.056 1.756 Comparative ExampleE 0.160 0.273 41.489 1.709 Comparative Example F 0.24 0.37 33.87 1.51Comparative Example G 0.24 0.41 41.27 1.70 Comparative Example H 0.270.39 30.91 1.45 Comparative Example I 0.26 0.39 34.48 1.53 ComparativeExample J 0.21 0.41 49.32 1.97 Comparative Example K 0.44 0.63 29.411.42 Example 3 0.417 0.690 39.69 1.655 Example 4 0.444 0.714 37.77 1.607Comparative Example L 0.278 0.488 43.065 1.756 Comparative Example M0.308 0.541 43.07 1.757 Comparative Example N 0.323 0.556 41.93 1.722Comparative Example O 0.323 0.541 40.32 1.676 Comparative Example P0.286 0.513 44.28 1.795 Comparative Example Q 0.408 0.667 38.77 1.633Example 5 0.429 0.667 35.714 1.556 Comparative Example R 0.217 0.37542.029 1.725 Comparative Example S 0.224 0.395 43.284 1.763 ComparativeExample T 0.238 0.395 39.683 1.658 Comparative Example U 0.238 0.39539.683 1.658 Comparative Example V 0.188 0.375 50.000 2.000 ComparativeExample W 0.435 0.667 34.783 1.533

Example 7: Angle of Repose

The angle of repose has been used to characterize the flow properties ofsolids. Angle of repose is a characteristic related to interparticulatefriction or resistance to movement between particles. The angle ofrepose is a constant, three-dimensional angle (relative to thehorizontal base) assumed by a cone-like pile of material.

Procedure (as Per USP General Chapter <1174>):

The angle of repose is formed on a fixed base with a retaining lip toretain a layer of powder on the base. The base should be free ofvibration. The height of the funnel is varied to carefully build up asymmetrical cone of powder. Care should be taken to prevent vibration asthe funnel is moved. The funnel height should be maintainedapproximately 2-4 cm from the top of the powder pile as it is beingformed in order to minimize the impact of falling powder on the tip ofthe cone. If a symmetrical cone of powder cannot be successfully orreproducibly prepared, this method is not appropriate. The angle ofrepose is determined by measuring the height of the cone of powder andcalculating the angle of repose (a) from the following equation: tan(a)=height/0.5 base.

Results:

Angle of repose Flow Formulations (degree) behavior Example 1 34 GoodExample 2 36.66 Fair Comparative Example A These formulations didComparative Example B not pass through the funnel as Comparative ExampleC such due to Comparative Example D rat hole Comparative Example Eformation and Comparative Example F poor flow Comparative Example Gproperties and hence Comparative Example H could not Comparative ExampleI be analyzed Comparative Example J Comparative Example K 41.10 weakExample 3 34 Good Example 4 35 Good Comparative Example L 37 FairComparative Example M Formulations did not pass through ComparativeExample N the funnel as such due to rat hole formation and poor flowproperties and hence could not be analyzed Comparative Example O 36 FairComparative Example P Formulations did not pass through the funnel assuch due to rat hole formation and poor flow properties and hence couldnot be analyzed Comparative Example Q 32 Good Example 5 31 GoodComparative Example R 36 Fair Comparative Example S Formulations did notpass through the funnel as such due to rat hole formation and poor flowproperties and hence could not be analyzed Comparative Example T 36 FairComparative Example U 37 Fair Comparative Example V Formulations did notpass through the funnel as such due to rat hole formation and poor flowproperties and hence could not be analyzed Comparative Example W 35 Good

Example 8: Moisture Content

The pharmaceutical formulations were placed in open petri dishes, whichwere then placed in a Climacel maintained at 25° C./75% RH forsimulating exposure to high humidity. The moisture content of eachformulation was analyzed after 1, 2 and 6 hours in the Climacel.Moisture content was evaluated by using USP General Chapter 921—WaterDetermination method.

Results:

Moisture Content (wt %) Formulations Initial 1 hour 2 hours 6 hoursExample 1 1.19 2.27 3.65 6.82 Example 2 1.49 3.08 5.80 7.88 ComparativeExample A 4.24 5.33 8.10 12.49 Comparative Example B 4.40 5.12 8.3113.11 Comparative Example C 4.57 5.77 6.98 13.28 Comparative Example D4.11 5.45 8.67 14.54 Comparative Example E 4.34 5.48 7.96 13.64Comparative Example F 5.30 6.97 10.60 14.54 Comparative Example G 5.318.16 11.65 15.23 Comparative Example H 4.95 7.77 9.96 14.11 ComparativeExample I 5.10 7.91 9.78 14.23 Comparative Example J 6.32 9.00 10.9214.57 Comparative Example K 1.66 4.60 5.86 9.77 Example 3 2.1 3.01 4.4510.95 Example 4 2.09 2.89 4.68 11.39 Comparative Example L 4.73 6.729.12 14.24 Comparative Example M 4.08 5.94 7.57 12.92 ComparativeExample N 4.07 6.69 7.9 12.75 Comparative Example O 4.1 5.83 8.26 13.43Comparative Example P 4.03 6.54 8.54 13.41 Comparative Example Q 2.053.2 4.86 12.06 Example 5 1.17 2.98 3.8 5.65 Comparative Example R 4.6510.19 14.64 13 Comparative Example S 4.46 13.56 10.87 13.26 ComparativeExample T 4.14 10.24 10.11 13.42 Comparative Example U 4.62 14.82 8.5910.14 Comparative Example V 4.95 12.68 8.58 12.42 Comparative Example W1.94 2.49 3.11 8.37

Example 9: Anti-Sticking Properties

The anti-sticking properties of the formulation was measured bydetermining the residual content using the following procedure:

Procedure:

The pharmaceutical formulations were filled uniformly in 10 stick packsmade from flexible laminates as depicted in FIG. 5. The fill weight ofeach stick pack was noted down for further reference. Filled stick packswere sealed using a sealing machine. The sealed stick packs were kept onvibratory shifter for 30 minutes for entrapping the formulations intothe corners of the stick pack. Each stick pack was opened by cuttingfrom one sealed side. The formulation from each stick pack was removedand weighed on a calibrated balance to measure the amount of formulationrecovered from each stick pack. The residual content was calculatedusing the following formula:

(Fill weight of stick pack)−(Content recovered from stick pack)=Residualcontent

Results

Formulations % Residual content Standard Deviation Example 1 2.04 0.39Example 2 1.35 0.35 Comparative Example A 6.49 1.14 Comparative ExampleB 4.98 0.99 Comparative Example C 7.39 0.73 Comparative Example D 5.111.03 Comparative Example E 4.10 0.99 Comparative Example F 4.76 0.80Comparative Example G 4.75 0.91 Comparative Example H 4.02 0.56Comparative Example I 4.04 0.34 Comparative Example J 3.02 2.20Comparative Example K 1.94 0.50 Example 3 0.63 0.11 Example 4 0.6 0.11Comparative Example L 2.28 0.86 Comparative Example M 2.78 0.57Comparative Example N 2.08 0.43 Comparative Example O 2.25 0.34Comparative Example P 1.42 0.65 Comparative Example Q 0.96 0.20 Example5 2.15 0.22 Comparative Example R 4.72 1.22 Comparative Example S 8.193.88 Comparative Example T 10.65 4.50 Comparative Example U 10.68 5.85Comparative Example V * Wet Mass with very poor flow Comparative ExampleW 4.73 3.09

1. A free-flowing solid pharmaceutical formulation comprising one ormore active ingredients and a blend composition comprising sorbitol andliquid paraffin.
 2. The formulation according to claim 1 wherein theblend composition further comprises citric acid.
 3. The formulationaccording to claim 1, comprising 0.01% to 30% by weight of activeingredient(s), 70% to 99.99% by weight of the blend composition, and 0%to 30% by weight of other pharmaceutically acceptable excipients.
 4. Theformulation according to claim 3 comprising 0.1% to 28% by weight ofactive ingredient(s), 72% to 99.9% by weight of the blend composition,and 5% to 30% by weight of one or more other pharmaceutically acceptableexcipients.
 5. The formulation according to claim 1, wherein the blendcomposition comprises 95 to 99.9% by weight of sorbitol, 0.1% to 5% byweight of liquid paraffin, and 0 to 4% by weight of citric acid.
 6. Theformulation according to claim 5 wherein the blend composition comprises96 to 99.5% by weight of sorbitol, 0.5% to 4% by weight of liquidparaffin, and 0.5 to 2% by weight of citric acid.
 7. The formulationaccording to claim 5 wherein the blend composition consists of 95 to99.9% by weight of sorbitol, 0.1% to 5% by weight of liquid paraffin,and 0 to 4% by weight of citric acid.
 8. The formulation according toclaim 7 wherein the blend composition consists of 96 to 99.5% by weightof sorbitol, 0.5% to 4% by weight of liquid paraffin, and 0.5 to 2% byweight of citric acid.
 9. The formulation according to claim 1, whereinthe active ingredient is selected from the group consisting ofdesloratadine, montelukast, solifenacin, silodosin, sildenafil, andpharmaceutically acceptable salts thereof.
 10. The formulation accordingto claim 1, wherein the active ingredient is desloratadine.
 11. Theformulation according to claim 1, wherein the active ingredient issildenafil.
 12. The formulation according to claim 1, wherein the activeingredient is solifenacin.
 13. A package containing the formulationaccording to claim
 1. 14. The package according to claim 13 selectedfrom the group consisting of a sachet and a stick pack. 15-22.(canceled)
 23. A process manufacturing a pharmaceutical formulationaccording to claim 1, comprising: (a) forming a lyophilized powder bysubliming solvent from a preparation comprising one or more activeingredients and the solvent; (b) forming a blend composition comprisingsorbitol, liquid paraffin and, optionally, citric acid; (c) mixing theblend composition obtained in step (b) with the lyophilized powderobtained in step (a).
 24. The process according to claim 23, wherein theblend composition comprises citric acid.
 25. The process according toclaim 23, wherein the blend composition comprises 95 to 99.9% by weightof sorbitol, 0.1% to 5% by weight of liquid paraffin, and 0 to 4% byweight of citric acid.
 26. The process according to claim 23, whereinthe blend composition consists of 95 to 99.9% by weight of sorbitol,0.1% to 5% by weight of liquid paraffin, and 0 to 4% by weight of citricacid.
 27. The process according to claim 23, wherein the activeingredient is selected from the group consisting of desloratadine,montelukast, solifenacin, silodosin, sildenafil, and pharmaceuticallyacceptable salts thereof.